The present invention is directed to certain isoxazolone compounds that inhibit the release of inflammatory cytokines such as interleukin-1 (1L-1) and tumor necrosis factor (TNF) from cells. The compounds of the invention, therefore, are useful in treating diseases involving unwanted cytokine activity.
Many cytokine-mediated diseases and conditions are associated with excessive or unregulated production or activity of one or more cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 8 (IL-8). IL-1 and TNF are important proinflammatory cytokines, which along with several other related molecules, mediate inflammatory cellular response in a wide variety of diseases and conditions. Proinflammatory cytokines such as IL-1 and TNF stimulate other inflammatory mediators such as nitric oxide, cyclooxygenase-2, matrix metalloproteinases. The inhibition of these cytokines is consequently both directly and indirectly beneficial in controlling, reducing and alleviating many of these disease states.
Elevated levels of proinflammatory cytokines are implicated in many disease states, including rheumatoid arthritis (Dinarello, C. A., et al. 1984, Rev. Infect. Disease 6:51; Maini, R. E. 1999, The Lancet 354:1932; Weinblatt, M. E. 1999, New Eng. J. Med. 340:253), osteoarthritis (Pelletier and Pelletier 1989, J. Rheum. 16:19; Pelletier, et al. 1993, Am. J. Path. 142:95; Farahat, et al. 1993, Ann. Rheum. Dis. 52:870; Tiku, et al. 1992, Cell Immunol. 140:1; Webb, et al. 1997, O. and C. 5:427; Westacott, et al. 2000, O. and C. 8:213), diabetes (McDaniel, et al. 1996, Proc. Soc. Exp. Biol. Med. 211:24), HIV/AIDS (Kreuzer, et al. 1997, Clin. Exp. Immunol. 45:559), acute and chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, Crohn""s disease and ulcerative colitis (Rankin, E. C. C., et al. 1997, British J. Rheum. 35:334; Stack, W. A., et al. 1997, The Lancet 349:521); congestive heart failure Han et al. 2000, Trends Cardiovasc. Med. 10:19; Hunter et al. 1999, N. Engl. J. Med. 341:1276; Behr et al. 2000, Circ. 102:II-289;Shimamoto et al. 2000, Circ:102:II-289; Aukrust et al. 1999, Am. J. Cardiol. 83:376, hypertension (Singh, et al. 1996 J. Hypertension 9:867), chronic obstructive pulmonary disease, septic shock syndrome (Dinarello, C. A. 1995, Nutrition 11:492), tuberculosis, adult respiratory distress, asthma (Renzetti, et al. Inflammation Res. 46:S143), atherosclerosis (Elhage, et al. 1998, Circulation 97:242), muscle degeneration, periodontal disease (Howells 1995, Oral Dis. 1:266), cachexia, Reiter""s syndrome, gout, acute synovitis, eating disorders including anorexia and bulimia nervosa (Holden, et al. 1996, Med. Hypothesis 47:423), fever, malaise, myalgia and headaches (Beisel 1995 Am. J. Clin. Nutr. 62:813). Inhibition of proinflammatory cytokine production, therefore, may offer the opportunity to treat or prevent a wide range of diseases and conditions involving elevated levels of proinflammatory cytokines.
Numerous small molecule inhibitors of cytokine production have been disclosed. (See Salituro, F. G. et al. 1999, 6, 807-823 and references cited therein). In particular, 1,2,4-triazoles (WO 00/10563 and WO 97/47618), isoxazoles (WO 01/12621), and imidazoles (WO 00/26209, WO 99/03837 and references therein) have been disclosed. However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have recently been reported (Foster, M. L. et al., Drug News Perspect, 2000, 13(8), 488-497 and Adams, J. L. et al., Bioorg Med Chem Lett, 1998, 8, 3111-3116). In light of the this potential toxicity and the risks associated with developing human drugs, a continuing need exists for potent new small molecule inhibitors of cytokine production with improved pharmacokinetic and safety profiles.
All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
The invention provides compounds which are potent cytokine inhibitors and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention is directed to compounds having a structure according to Formula (I): 
wherein R1, m, A, B, and are defined herein.
The invention also includes optical isomers, diastereomers, and enantiomers of the structure above, and pharmnaceutically-acceptable salts thereof.
The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted cytokine activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for diseases associated with unwanted cytokine activity using these compounds or the compositions comprising them.
The invention is directed to a novel group of compounds which are potent inhibitors of cytokines and which are effective in treating conditions characterized by excess activity of these enzymes.
Terms and Definitions
xe2x80x9cAlkenylxe2x80x9d is a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms and at least one (preferably only one) carbonxe2x80x94carbon double bond. Alkenyl groups may be straight or branched. Preferred branched alkenyl groups have one or two branches, preferably one branch. Alkenyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkenyl groups have 1 to 3 substituents unless otherwise specified. Alkenyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkenyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term xe2x80x9clower alkenylxe2x80x9d refers to an alkenyl group having from 2 to 6, preferably from 2 to 4, carbon atoms.
xe2x80x9cAlkylxe2x80x9d is a monovalent saturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6 carbon atoms. Alkyl groups may be straight or branched. Preferred branched alkyl groups have one or two branches, preferably one branch. Alkyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkyl groups have 1 to 3 substituents unless otherwise specified. Alkyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term xe2x80x9clower alkylxe2x80x9d refers to an alkyl group having from 1 to 6, preferably from 1 to 4, carbon atoms.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x94OR where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl. Preferred alkoxy groups include methoxy, ethoxy, and iso-propoxy.
xe2x80x9cAlkynylxe2x80x9d is a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms and at least one (preferably only one) carbonxe2x80x94carbon triple bond. Alkynyl groups may be straight or branched. Preferred branched alkynyl groups have one or two branches, preferably one branch. Alkynyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkynyl groups have 1 to 3 substituents unless otherwise specified. Alkynyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkynyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term xe2x80x9clower alkynylxe2x80x9d refers to an alkynyl group having from 2 to 6, preferably from 2 to 4, carbon atoms.
xe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94N(R)2 where each R is independently chosen from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl. Preferred amino groups include NH2, NHCH3, and NHC(O)CH3.
xe2x80x9cArylxe2x80x9d is an aromatic hydrocarbon ring system. Aryl rings are either monocyclic ring systems or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms, more preferably 10 carbon atoms, in the ring. Bicyclic aryl rings include ring systems wherein both rings are aromatic or only one ring is aromatic. Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring is phenyl. Aryl rings may be unsubstituted or substituted with from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2 substituents on the ring. Preferred aryl rings are unsubstituted or substituted with 1 or 2 substituents. Aryl rings may be substituted with halo, cyano, nitro, hydroxy, amino, alkyl, lower alkenyl, lower alkynyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy [which refers to the group (xe2x80x94OCH2Oxe2x80x94)], thioalkoxy, thioaryloxy, or any combination thereof. Preferred aryl ring substituents include halo, cyano, amino, alkyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy.
xe2x80x9cAryloxyxe2x80x9d refers to the group xe2x80x94OR where R is aryl or heteroaryl. Preferred aryloxy groups include phenoxy and pyridinyloxy.
xe2x80x9cCyanoxe2x80x9d refers to the group xe2x80x94CN.
xe2x80x9cCycloalkylxe2x80x9d is a saturated hydrocarbon ring. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Preferred cycloalkyl rings are monocyclic. Monocyclic cycloalkyl rings contain from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms, more preferably 3, 5, or 6 carbon atoms in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, heterocycloalkyl, halo, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred cycloalkyl group substituents include halo, hydroxy, alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, amino, and keto. More preferred cycloalkyl group substituents include hydroxy, alkyl, and alkoxy.
xe2x80x9cCycloalkenylxe2x80x9d is an unsaturated hydrocarbon ring. Cycloalkenyl rings are not aromatic and contain at least one (preferably only one) carbonxe2x80x94carbon double bond. Cycloalkenyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Preferred cycloalkenyl rings are monocyclic. Monocyclic cycloalkenyl rings contain from 5 to 10 carbon atoms, preferably from 5 to 7 carbon atoms, more preferably 5 or 6 carbon atoms in the ring. Bicyclic cycloalkenyl rings contain from 8 to 12 carbon atoms in the ring. Preferred bicyclic cycloalkenyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Cycloalkenyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkenyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, heterocycloalkyl, halo, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred cycloalkenyl group substituents include halo, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. More preferred cycloalkyl group substituents include OH, alkyl, alkoxy, and keto.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo. More preferred halo are chloro and fluoro, especially fluoro.
xe2x80x9cHeteroalkenylxe2x80x9d is a monovalent chain having 3 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 3 to 12, more preferably 3 to 6 member atoms and at least one (preferably only one) carbonxe2x80x94carbon double bond. Heteroalkenyl chains have at least one heteroatom member atom. Heteroalkenyl groups may be straight or branched. Preferred branched heteroalkenyl groups have one or two branches, preferably one branch. Heteroalkenyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkenyl groups have 1 to 3 substituents unless otherwise specified. Heteroalkenyl group substituents include halo, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkenyl group substituents include halo, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term xe2x80x9clower heteroalkenylxe2x80x9d refers to a heteroalkenyl group having from 3 to 6, preferably from 3 to 4, member atoms.
xe2x80x9cHeteroalkylxe2x80x9d is a monovalent saturated chain having from 2 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 12, more preferably 2 to 6. Heteroalkyl chains have at least one heteroatom member atom. Heteroalkyl groups may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl groups have 1 to 3 substituents unless otherwise specified. Heteroalkyl group substituents include aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, cycloalkyl, heterocycloalkyl, halo, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkyl group substituents include aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, halo, hydroxy, amino, and keto. The term xe2x80x9clower heteroalkylxe2x80x9d refers to a heteroalkyl group having from 2 to 6, preferably from 2 to 4, member atoms.
xe2x80x9cHeteroalkynylxe2x80x9d is a monovalent chain having 3 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 3 to 12, more preferably 3 to 6 member atoms and at least one (preferably only one) carbonxe2x80x94carbon triple bond. Heteroalkynyl chains have at least one heteroatom member atom. Heteroalkynyl groups may be straight or branched. Preferred branched heteroalkynyl groups have one or two branches, preferably one branch. Heteroalkynyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkynyl groups have 1 to 3 substituents unless otherwise specified. Heteroalkynyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, cycloalkyl, heterocycloalkyl, halo, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkynyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, halo, hydroxy, amino, and keto. The term xe2x80x9clower heteroalkynylxe2x80x9d refers to a heteroalkynyl group having from 3 to 6, preferably from 3 to 4, member atoms.
xe2x80x9cHeteroarylxe2x80x9d is an aromatic ring containing carbon atoms and from 1 to 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused polycyclic ring systems. Monocyclic heteroaryl rings contain from 5 to 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Polycyclic heteroaryl rings contain 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Polycyclic heteroaryl rings include ring systems wherein at least one ring is heteroaryl (the second ring may be aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkyl). Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Preferred heteroaryl rings include, but are not limited to, the following rings: 
Heteroaryl rings may be unsubstituted or substituted with from 1 to 4, preferably from 1 to 3, more preferably from 1 to 2, substituents on the ring. Preferred heteroaryl rings are unsubstituted or substituted with 1 or 2 substituents. Heteroaryl rings may be substituted with halo, cyano, nitro, hydroxy, amino, alkyl, lower alkenyl, lower alkynyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy, or any combination thereof. Preferred heteroaryl ring substituents include halo, cyano, amino, alkyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy.
xe2x80x9cHeteroatomxe2x80x9d refers to a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
xe2x80x9cHeterocycloalkylxe2x80x9d is a saturated ring containing carbon atoms and from 1 to 4, preferably 1 to 3, heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro polycyclic ring systems. Monocyclic heterocycloalkyl rings contain from 3 to 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Polycyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Preferred polycyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Preferred heterocycloalkyl rings include but are not limited to the following: 
Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, cycloalkyl, halo, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heterocycloalkyl group substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, halo, hydroxy, amino, and keto.
xe2x80x9cKetoxe2x80x9d refers to the group xe2x95x90O.
xe2x80x9cNitroxe2x80x9d refers to the group xe2x80x94NO2.
xe2x80x9cOptical isomerxe2x80x9d, xe2x80x9cstereoisomerxe2x80x9d, and xe2x80x9cdiastereomerxe2x80x9d as referred to herein have the standard art recognized meanings (see, e.g., Hawley""s Condensed Chemical Dictionary, 11th Ed.). The illustration of derivatives of the compounds of the instant invention is not intended to be limiting. The application of useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.
A xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987 incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center where once there is none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan""s practice.
xe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94S(O)0-2R where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl. Preferred thioalkoxy groups include methanesulfonyl.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group xe2x80x94S(O)0-2R where R is aryl or heteroaryl. Preferred thioaryloxy groups include phenylsulfide, benzenesulfonyl and pyridinesulfonyl.
xe2x80x9cThioketoxe2x80x9d refers to the group xe2x95x90S.
Compounds
The invention is directed to compounds of Formula (I): 
In the above structure, each R1 is independently selected from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lower heteroalkenyl, lower heteroalkynyl, heterocycloalkyl, heteroaryl, halo, CN, OR4, SR4, S(O)R4, S(O)2R4, and NR4R5. Preferred R1 is lower alkyl, halo, CN, OR4, and NR4R5. More preferred R1 is lower alkyl, halo, and CN.
In the above structure, m is an integer from 0 to 5. Preferred m is 0 to 3. More preferred m is 1 or 2.
In the above structure, Q is selected from the group consisting of 
Each R is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, halo, OH, CN, OR4, SR4, S(O)R4, S(O)2R4, and NR4R5. Preferred R2 is H, and halo. More preferred R2 is H.
R3 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, halo, OH, CN, OR4, SR4, S(O)R4, and S(O)2R4. Preferred R3 is H, alkyl, halo, OR4, NR4R5, SR4, S(O)R4, S(O)2R4. More preferred R3 is H, oR4, NR4R5.
X is selected from the group consisting of: CR3 and N. Preferred X is CR2. The most preferred X is CH.
Y is selected from the group consisting of: CR and N. Preferred Y is CH and N.
Z is selected from the group consisting of NR4, O, and S.
In the above structure, A is selected from the group consisting of: C(O) and Nxe2x80x94G.
In the above structure, B is selected from the group consisting of: C(O) and Nxe2x80x94G.
Provided that one and only one of A or B is C(O).
In the above structure, G is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR4, S(O)2R4. Preferred G is alkyl, alkynyl, aryl, heteroalkyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR4, S(O)2R4. More preferred G is substituted alkyl (wherein the preferred substituents are keto, alkoxy, aryloxy, amino, heteroaryl, heterocycloalkyl) and aryl.
Each R4 is independently selected from H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl. Preferred R4 is H, lower alkyl, heteroalkyl, aryl, and heteroaryl.
Each R5 is independently selected from H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, OR4, and S(O)2R4. Preferred R5 is H, lower alkyl, and S(O)2R4.
While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy and amino groups as stated above, the following are not envisioned in the invention:
1. Enols (OH attached to a carbon bearing a double bond).
2. Amino groups attached to a carbon bearing a double bond (except for vinylogous amides).
3. More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring).
4. Hydroxy, amino, or amido attached to a carbon that also has a heteroatom attached to it.
5. Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it.
Compound Preparation
The compounds of the invention can be prepared using conventional organic syntheses. Particularly preferred syntheses are carried out according to the following general reaction schemes, Schemes 1, 2, 3, 4 and 5. Scheme 1 describes a general reaction scheme for making compounds of the invention wherein xe2x80x9cAxe2x80x9d is C(O) and xe2x80x9cQxe2x80x9d is either a 5- or 6-membered heteroaryl ring. Scheme 2 describes a general reaction scheme for making compounds of the invention wherein xe2x80x9cAxe2x80x9d is C(O) and xe2x80x9cQxe2x80x9d is a specifically a 6-membered heteroaryl ring. Scheme 3 describes a general reaction scheme for making compounds of the invention wherein xe2x80x9cBxe2x80x9d is C(O) and xe2x80x9cQxe2x80x9d is either a 5- or 6-membered heteroaryl ring. Scheme 4 describes a general reaction scheme for making compounds of the invention wherein xe2x80x9cAxe2x80x9d is C(O) and xe2x80x9cQxe2x80x9d is specifically a 5-membered ring. Scheme 5 describes a general reaction scheme for making compounds of the invention wherein xe2x80x9cAxe2x80x9d is C(O), xe2x80x9cQxe2x80x9d is 5- or 6-membered heteroaryl ring, and xe2x80x9c0xe2x80x9d is a heteroalkyl substituent. 
In Scheme 1, R1, m, G and Q are as defined above. Substituted heterocycles of type S1b and esters of type S1a are either commercially available as starting material or are made from commercially available starting materials using methods known to one of ordinary skill in the art. Coupling of S1a with S1b to form P-hydroxyester S1c is accomplished using the method described by Smith, A. B. III et al. (Synthesis 1981, 567-570). Oxidation of alcohol S1c with chromium (VII) oxide provides ketone S1d. Cyclocondensation of xcex2-ketoester S1d with hydroxylamine is carried out at 90xc2x0 C. in pyridine to give the disubstituted isoxazolone S1e. Elaboration of isoxazolone S1e is accomplished under a variety of conditions to provide access to a wide variety of functionalized isoxazolones of type S1f. For example, acylation of S1e with acyl halides and tertiary amine base gives amides. Reaction of S1e with carbamoyl chlorides gives ureas. Copper-mediated coupling of Sle with aryl boronic acids gives aryl amines. Reaction of S1e with sulfonyl chlorides and tertiary amine bases gives sulfonamides. 
In Scheme 2, R1, R2, R3, m, G, X, and Y are as defined above. Rxe2x80x2 and Rxe2x80x3 are each appropriate functional groups which enable the skilled artisan to functionalize the six-membered heterocycle to ultimately form a compound according to the invention. To further elaborate the isoxazolone scaffold, Rxe2x80x2 and Rxe2x80x3 on S2d may be exchanged for a wide variety of functional groups (R2 and R3). In practice two approaches are used. In the first approach, isoxazolones of type S2d are substituted at the isoxazolone nitrogen position as described in Scheme 1 to give S2e. When either Rxe2x80x2 or Rxe2x80x3 is xe2x80x94SMe, isoxazolone S2d is oxidized specifically to either the corresponding sulfoxide or the sulphone (not shown) with several different commonly-used reagents (e.g., peracetic acid,
3-chloroperbenzoic acid, or potassium peroxymonosulfate). Either the sulfoxide or the corresponding sulphone is then displaced under nucleophilic conditions to give compounds of type S2f. In the second approach, S2d (where Rxe2x80x2 and/or Rxe2x80x3 is xe2x80x94SMe) is first oxidized specifically to either the sulfoxide or the sulphone. The sulfoxide or the sulphone then undergoes nucleophilic substitution (replacement of Rxe2x80x2 for R3 and/or Rxe2x80x3 for R2), followed by the previously described electrophilic substitution of the isoxazolone ring to give compounds of type S2f. Using either approach, Rxe2x80x2 and/or Rxe2x80x3 may be xe2x80x94SMe, halo, or some other substituent capable of being displaced by R2 or R3. Furthermore, use of halo for Rxe2x80x2 and/or Rxe2x80x3 precludes the additional step of oxidizing the respective Rxe2x80x2 and/or Rxe2x80x3 to a better leaving group. 
In Scheme 3, R1, m and Q are as defined above. Substituted heterocyclic amides S3b are readily prepared from commercially available acid chlorides of type S3a. Coupling of S3b and 6-membered heterocycles of type S3c to form S3d is accomplished using a known method (Liverton, N. J. et. al. J. Med. Chem. 1999, 42, 2180-2190). An analogous coupling of S3b and 5-membered heterocycles of type S3c is accomplished using similar methods (oxazoles: see Evans, D. A., Cee, V. J., Smith, T. E., Santiago, K. J. Org. Lett. 1999, 1, 87-90; imidazoles: see Heterocycles, 1989, 29, 1551-1558). Deprotonation of ketone S3d with potassium bis(trimethylsilyl)amide (xe2x80x9cKHMDSxe2x80x9d) and quenching of the resulting enolate with ethylchloroformate provides xcex2-ketoester S3e. Cyclocondensation of xcex2-ketoester S3e with hydroxylamine provides the disubstituted isoxazolone of type S3f. Elaboration of isoxazolone S3f is accomplished according to previously mentioned procedures. 
In Scheme 4, R, R3, m, G, X, and Z are as defined above. Aldehydes of type S4b are either commercially available as starting material or are made from commercially available starting materials using methods disclosed in the literature (see Shafer, C. M. J. 10 Org. Chem. 1998, 63, 551-555 and references therein). Coupling of S4a and S4b to form S4c followed by oxidation and cyclocondensation with hydroxylamine to give S4d is accomplished as described in Schemes 1 and 2. Oxidation to sulfone S4e using literature procedure is followed by elaboration of the isoxazolone scaffold to S4f as described in Scheme 2. 
In Scheme 5, R1, R2, R3, m and Q are as defined above. Substituted isoxazolones S5a are prepared in the manner previously described in Schemes 1, 2, 3 and 4. Alkylation of S5a with allyl bromide provides isoxazolone S5b. Oxidative cleavage of the alkene S5b with osmium tetraoxide and sodium periodate gives aldehyde S5c. Reductive amination of aldehyde S5c is accomplished with sodium cyanoborohydride to provide access to a wide variety of functionalized heteroalkyl substituted isoxazolones of type S5d.
In Schemes 1, 2, 3, 4 and 5, the steps may be varied to increase the yield of the desired product. The skilled artisan will recognize the judicious choice of reactants, solvents, and temperatures is an important component in any successful synthesis. Determination of optimal conditions, solvents, reaction times, and amounts is routine. Thus the skilled artisan can make a variety of compounds using the guidance of the schemes above.
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other art that the skilled artisan is aware of.
The skilled artisan will also readily appreciate that certain reactions are best carried out when another potentially reactive functionality on the molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.
In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.